JP5094150B2 - Blood sugar level rise inhibitor - Google Patents
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- JP5094150B2 JP5094150B2 JP2007028813A JP2007028813A JP5094150B2 JP 5094150 B2 JP5094150 B2 JP 5094150B2 JP 2007028813 A JP2007028813 A JP 2007028813A JP 2007028813 A JP2007028813 A JP 2007028813A JP 5094150 B2 JP5094150 B2 JP 5094150B2
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Description
本発明は、食後の血糖値の一時的な上昇を効果的に抑制することができる血糖値上昇抑制剤に関する。 The present invention relates to a blood glucose level increase inhibitor that can effectively suppress a temporary increase in blood glucose level after a meal.
我が国の糖尿病の罹患者数は、全国統計(2004年)では約740万人、その予備軍も含めると1620万人と言われ(厚生労働省 平成14年糖尿病実態調査)、前回調査(平成9年)より20%増加している。死亡の直接的原因としては、糖尿病は男性で第10位、女性で第9位(厚生労働省 平成17年人口動態統計の概況)であるが、糖尿病との合併症によって誘発される大血管障害などを含めると更に深刻な数になると考えられている。特に、大血管障害では、血糖値の恒常値(空腹時の血糖値)の高さよりも食後の血糖値の一時的な上昇に原因があるとされており、この大血管障害を予防するためには、食後の血糖値の上昇、特に最高値を抑制することが最も効果的である。 The number of people with diabetes in Japan is approximately 7.4 million in national statistics (2004), and it is said that 16.2 million including the reserve army (Ministry of Health, Labor and Welfare 2002 Diabetes Survey), last survey (1997) ) By 20%. As a direct cause of death, diabetes is the 10th place for men and the 9th place for women (Ministry of Health, Labor and Welfare, 2005 overview of demographic statistics), but macrovascular disorders induced by complications with diabetes, etc. It is thought that the number will be even more serious if the number is included. In particular, macrovascular disorders are said to be caused by a temporary increase in blood glucose level after meals rather than a high blood glucose level (fasting blood sugar level). To prevent this macrovascular disorder It is most effective to suppress the increase in blood glucose level after meals, especially the highest value.
この点に関して、従来、食事の糖類の摂取を忌避する方法が長い間採られてきたが、近年は、糖類の単純な忌避ではなく、マルチトールやアステルパームなどの代替甘味料を利用した血糖値上昇の抑制が図られている。これらの代替甘味料は、優れた甘味の強さを有するが、味質の点で満足せず、その用途によっては砂糖を代替甘味料に置き換えたくないとの要望が強い。 In this regard, methods for avoiding dietary sugar intake have long been used, but in recent years blood sugar levels using alternative sweeteners such as maltitol and aster palm are not simple avoidance of sugar. The rise is suppressed. Although these alternative sweeteners have excellent sweetness strength, they are not satisfactory in terms of taste quality, and there is a strong demand for not replacing sugar with alternative sweeteners depending on their use.
かかる要望に答えるため、砂糖の味覚を損わずに血糖値の上昇を抑制する方法が提案されている。例えば特許文献1では、D−キシロースやL−アラビノースなどの砂糖分解酵素の阻害剤を食事と共に摂取する方法が提案されており、そこでは、コーヒーやオレンジジュースにD−キシロースやL−アラビノースを添加したものを摂取すると、食後の血糖値の上昇が緩やかになることが記載され、また、D−キシロースやL−アラビノースはそれ自体の味質も砂糖に近く、砂糖の味覚を損わないことが記載されている。 In order to respond to such a demand, a method for suppressing an increase in blood sugar level without impairing the taste of sugar has been proposed. For example, Patent Document 1 proposes a method of ingesting sugar-degrading enzyme inhibitors such as D-xylose and L-arabinose together with meals, in which D-xylose and L-arabinose are added to coffee and orange juice. Ingestion of the processed foods is said to increase the blood glucose level after meals, and D-xylose and L-arabinose also have a taste similar to that of sugar, and do not impair the taste of sugar. Are listed.
しかしながら、特許文献1の方法では、D−キシロースやL−アラビノースは食事の糖分と同時に摂取されているため、D−キシロースやL−アラビノースが小腸に到達してそこに存在する砂糖分解酵素を阻害するまでに一定の時間がかかり、血糖値上昇抑制効果を実際に発揮するまでに時間がかかった。 However, in the method of Patent Document 1, since D-xylose and L-arabinose are ingested simultaneously with the sugar content of the diet, D-xylose and L-arabinose reach the small intestine and inhibit the sugar-degrading enzyme present therein. It took a certain amount of time to do so, and it took time to actually demonstrate the blood glucose level increase suppressing effect.
一方、出願人は、この関連において、特許文献2において砂糖とL−アラビノースを共に有効成分とする糖尿病治療剤を既に提案した。この治療剤は、従来忌避されていた砂糖も有効成分としている点で画期的であるが、実際の人間の食事摂取時の好適な経口方法や血糖値低下効果に好適な砂糖の量については何ら具体的に提案していない。
本発明は、かかる従来技術の現状に鑑み創案されたものであり、その目的は、砂糖と砂糖分解酵素の不拮抗阻害剤を用いて食後の血糖値の上昇を効果的に抑制することができる血糖値上昇抑制剤を提供することにある。 The present invention was devised in view of the current state of the prior art, and the purpose thereof is to effectively suppress an increase in blood glucose level after a meal using a non-competitive inhibitor of sugar and saccharolytic enzyme. The object is to provide a blood sugar level increase inhibitor.
本発明者らは、かかる目的を達成するために腸管内での砂糖の吸収分解機構について鋭意研究した結果、砂糖の吸収分解が効果的に阻害されるためには、腸管内でD−キシロースやL−アラビノースなどの砂糖分解酵素阻害剤と基質の砂糖と小腸粘膜刷子縁膜に存在する砂糖分解酵素(スクラーゼ)とが複合体を形成していわゆる不拮抗型の阻害を発現していることが必要であり、この複合体の十分な形成には砂糖分解酵素阻害剤と基質の砂糖を摂取してから一定の時間がかかること、そして一旦複合体が形成されると、その解離が起こりにくく阻害効果が長時間持続すること、また小腸粘膜刷子縁膜に存在する有限量の砂糖分解酵素を阻害するためにはそれに対応して比較的多量の砂糖が必要であることを見出し、本発明の完成に至った。 As a result of intensive studies on the absorption and decomposition mechanism of sugar in the intestinal tract in order to achieve such an object, the present inventors have found that in order to effectively inhibit the absorption and decomposition of sugar, D-xylose and A sugar-degrading enzyme inhibitor such as L-arabinose, a substrate sugar, and a sugar-degrading enzyme (sucrase) present in the small intestinal mucosa brush border membrane form a complex to express a so-called antagonistic inhibition. It is necessary, and sufficient formation of this complex takes a certain amount of time after ingesting the sugar-degrading enzyme inhibitor and the substrate sugar, and once the complex is formed, it is difficult to dissociate and inhibit Finding that the effect lasts for a long time and that a relatively large amount of sugar is required to inhibit a finite amount of sugar-degrading enzymes present in the small intestinal mucosa brush border membrane, the completion of the present invention It came to.
即ち、本発明によれば、食前10分〜6時間で経口摂取されることによって食後の血糖値の上昇を抑制する血糖値上昇抑制剤であって、砂糖分解酵素の不拮抗阻害剤と、1回の摂取あたり15g〜75g/回の砂糖とを有効成分として含有することを特徴とする血糖値上昇抑制剤が提供される。 That is, according to the present invention, a blood sugar level increase inhibitor that suppresses an increase in blood sugar level after meal by being orally ingested 10 minutes to 6 hours before a meal, There is provided a blood sugar level increase inhibitor characterized by containing 15 to 75 g / dose sugar as an active ingredient per ingestion.
本発明の血糖値上昇抑制剤の好ましい態様によれば、砂糖分解酵素の不拮抗阻害剤の含有量は、砂糖の4〜20重量%であり、砂糖分解酵素の不拮抗阻害剤は、L−アラビノース、D−タガトース、D−キシロース及びこれらの混合物からなる群から選択される。本発明の血糖値上昇抑制剤は、食品又は飲料の形態であることが好ましい。 According to a preferred embodiment of the blood sugar level increase inhibitor of the present invention, the content of the non-competitive inhibitor of sugar-degrading enzyme is 4 to 20% by weight of sugar, and the non-competitive inhibitor of sugar-degrading enzyme is L- Selected from the group consisting of arabinose, D-tagatose, D-xylose and mixtures thereof. The blood sugar level elevation inhibitor of the present invention is preferably in the form of food or beverage.
本発明の血糖値上昇抑制剤は、砂糖分解酵素の不拮抗阻害剤と十分な量の砂糖を有効成分として含有しているので、これらが腸管内で砂糖分解酵素と共に安定な複合体を形成することができ、結果として腸管での糖分の吸収分解を長時間阻害することができる。特に、本発明の血糖値上昇抑制剤は、腸管内で上述の複合体を形成させてから食事を摂取するようにしたので、腸管内に食事の糖分が到来してもその吸収分解を効果的に抑制することができる。 Since the blood sugar level increase inhibitor of the present invention contains a non-competitive inhibitor of sugar-degrading enzyme and a sufficient amount of sugar as active ingredients, these form a stable complex with the sugar-degrading enzyme in the intestine. As a result, absorption and decomposition of sugar in the intestinal tract can be inhibited for a long time. In particular, since the blood sugar level elevation inhibitor of the present invention takes the meal after the above complex is formed in the intestinal tract, even if the sugar content of the meal arrives in the intestinal tract, the absorption decomposition is effective. Can be suppressed.
本発明の血糖値上昇抑制剤は、砂糖分解酵素(スクラーゼ)の不拮抗阻害剤と比較的多量の砂糖とを有効成分として含有するものであり、基質である砂糖(S)が腸管内の砂糖分解酵素(E)と結合してES複合体を形成し、そこに阻害剤(I)が結合して立体的な変化を引き起こしてESI複合体を形成し、この複合体が砂糖分解酵素の活性を阻害することによって腸管内での砂糖の吸収分解及び血糖値の上昇を抑制することを特徴とする。本発明で使用する砂糖分解酵素の不拮抗阻害剤は、砂糖分解酵素に対して不拮抗阻害効果を持つものであればいずれも使用することができ、例えばL−アラビノース、D−タガトース、D−キシロースなどの糖質を使用することが好ましい。 The blood sugar level increase inhibitor of the present invention contains a non-competitive inhibitor of sugar-degrading enzyme (sucrase) and a relatively large amount of sugar as active ingredients, and the substrate sugar (S) is sugar in the intestinal tract. It binds to the degrading enzyme (E) to form an ES complex, and the inhibitor (I) binds to it to cause a steric change to form an ESI complex, which is the activity of the sugar degrading enzyme. It is characterized by suppressing the absorption and decomposition of sugar and the increase of blood sugar level in the intestinal tract by inhibiting the above. Any non-competitive inhibitor of the sugar-degrading enzyme used in the present invention can be used as long as it has an anti-competitive inhibitory effect on the sugar-degrading enzyme. For example, L-arabinose, D-tagatose, D- It is preferable to use a carbohydrate such as xylose.
本発明で使用する砂糖は、砂糖分解酵素の基質であり、砂糖分解酵素の不拮抗阻害剤が腸管内で砂糖分解酵素と結合して阻害作用を発揮するのに必要な成分である。本発明の血糖値上昇抑制剤における砂糖含有量は、驚くべきことに1回の摂取あたり15g〜75gと比較的多量である。好ましい砂糖含有量は1回摂取あたり25g〜65gであり、特に、1回摂取あたり30g〜55gである。1回あたりの砂糖の含有量が上記下限未満であると、腸管内の砂糖分解酵素と結合する砂糖が少なくなるため酵素阻害が十分になされず、血糖値上昇抑制効果が十分に発揮されないおそれがあり、また、1回あたりの砂糖の含有量が上記上限を超えると、1回の摂取で困難であると共に経済性に劣るため好ましくない。 Sugar used in the present invention is a substrate for a sugar-degrading enzyme, and is a component necessary for a non-competitive inhibitor of a sugar-degrading enzyme to bind to the sugar-degrading enzyme in the intestine and exert an inhibitory action. The sugar content in the blood sugar level elevation inhibitor of the present invention is surprisingly a relatively large amount of 15 to 75 g per ingestion. The preferred sugar content is 25 to 65 g per ingestion, especially 30 to 55 g per ingestion. If the sugar content per one time is less than the above lower limit, the amount of sugar that binds to the sugar-degrading enzyme in the intestinal tract decreases, so that the enzyme inhibition is not sufficient, and the blood glucose level increase suppressing effect may not be sufficiently exhibited. In addition, when the sugar content per one time exceeds the above upper limit, it is not preferable because it is difficult to take once and it is inferior in economic efficiency.
本発明の血糖値上昇抑制剤では、砂糖分解酵素の不拮抗阻害剤の含有量は、砂糖の含有量に応じて決定すればよく、砂糖の4〜20重量%、特に5〜15重量%であることが好ましい。砂糖分解酵素の不拮抗阻害剤の含有量が上記下限未満であると、腸管内で砂糖及び砂糖分解酵素と共に十分な量の複合体を形成せず、血糖値上昇抑制効果が十分に発揮できないおそれがあり、また、上記上限を超えると1回に摂取する不拮抗阻害剤の量が多くなり、下痢などを引起すおそれがあり、好ましくない。 In the blood sugar level increase inhibitor of the present invention, the content of the non-competitive inhibitor of sugar-degrading enzyme may be determined according to the content of sugar, and is 4 to 20% by weight, particularly 5 to 15% by weight of sugar. Preferably there is. If the content of the non-competitive inhibitor of saccharolytic enzyme is less than the above lower limit, a sufficient amount of complex may not be formed with sugar and saccharolytic enzyme in the intestinal tract, and the effect of suppressing the increase in blood sugar level may not be fully exhibited. In addition, if the above upper limit is exceeded, the amount of non-competitive inhibitor taken at a time increases, which may cause diarrhea and the like, which is not preferable.
本発明の不拮抗阻害剤を利用した砂糖分解酵素の活性の阻害には、砂糖が腸管に到達してそこで砂糖分解酵素と結合し、それにさらに砂糖分解酵素の不拮抗阻害剤が結合して複合体を形成することが必要であり、そのためには一定の時間がかかる。従って、本発明の血糖値上昇抑制剤は、腸管内で上記複合体を十分に形成させるため、食前に摂取するようにしており、具体的には食前10分〜6時間で、好ましくは食前30分〜5時間で、さらに好ましくは食前1時間〜4時間で経口摂取するようにしている。上記のように食前一定時間前からの摂取としたのは、これより短くすると十分な量の複合体が形成されない段階で食事の糖分が腸管に到達してしまうので、その吸収分解を効果的に阻害できないおそれがあるからである。また食前6時間までの摂取としたのは、後述の検証試験2の結果から、腸管内で複合体が形成されてから有効に維持される時間が6時間程度であると考えられるからである。 Inhibiting the activity of the sugar-degrading enzyme using the non-competitive inhibitor of the present invention involves the combination of sugar reaching the intestinal tract where it binds to the sugar-degrading enzyme, which is further combined with the non-competitive inhibitor of the sugar-degrading enzyme. It is necessary to form a body, which takes a certain amount of time. Therefore, in order to sufficiently form the above complex in the intestinal tract, the blood sugar level elevation inhibitor of the present invention is taken before meal, specifically 10 minutes to 6 hours before meal, preferably 30 before meal. It is intended to be taken orally in minutes to 5 hours, more preferably 1 hour to 4 hours before meals. As described above, the intake from a certain time before the meal was taken because the sugar content of the meal reaches the intestinal tract at a stage where a sufficient amount of the complex is not formed if it is shorter than this, so that the absorption decomposition is effectively performed. This is because there is a possibility that it cannot be inhibited. In addition, the reason for intake up to 6 hours before meals is that, based on the results of verification test 2 described later, it is considered that the time during which the complex is formed in the intestinal tract is effectively maintained for about 6 hours.
本発明の血糖値上昇抑制剤は、所望により上述の二つの有効成分以外に、摂取を容易にするための成分や血糖値上昇抑制効果をさらに高めるための成分を含むことができる。摂取を容易にするための成分としては、味質を整える効果を有するスクラロース、キシリトール、エリスリトールなどの代替甘味料が挙げられ、血糖値上昇抑制効果をさらに高めるための成分としては、砂糖分解酵素の不拮抗阻害剤の腸管内滞留時間を長くする効果を有するカラギーナン、寒天、植物ガム(グアガム、アラビアガム等)などの不溶性及び水溶性の食物繊維や増粘剤が挙げられる。 The blood sugar level increase inhibitor of the present invention can contain a component for facilitating ingestion and a component for further enhancing the blood sugar level increase suppressing effect, if desired, in addition to the above-mentioned two active ingredients. Ingredients for facilitating ingestion include alternative sweeteners such as sucralose, xylitol, and erythritol that have the effect of adjusting the taste. Ingredients for further enhancing the effect of suppressing the increase in blood glucose level include sugar-degrading enzymes. Examples thereof include insoluble and water-soluble dietary fibers and thickeners such as carrageenan, agar, and plant gums (such as guar gum and gum arabic) that have the effect of prolonging the intestinal residence time of noncompetitive inhibitors.
本発明の血糖値上昇抑制剤は、薬剤の形態に限定されるものではなく、食品又は飲料の形態であることができる。これらの形態にすることにより、摂取が一層容易になる。食品の形態としては、例えばアイスクリーム、ヨーグルト等の乳製品;飴、ガム、クッキー、ケーキ、プリン、ゼリー、ババロア、ムース、羊羹、饅頭、最中、どら焼き、たい焼き、回転焼き、煎餅、おはぎ、大福、団子、ぜんざいなどの和洋菓子類が挙げられ、飲料の形態としては、例えばコーヒー、紅茶、清涼飲料水、炭酸飲料水、果汁入り飲料水などが挙げられる。食品又は飲料の形態にするには、食品又は飲料の製造工程のいずれかで本発明の血糖値上昇抑制剤の有効成分を混入すればよい。この場合、有効成分の砂糖は、食品又は飲料中に本来含まれている砂糖を利用することができる。 The blood sugar level elevation inhibitor of the present invention is not limited to a drug form, and may be a food or beverage form. By taking these forms, ingestion becomes easier. Examples of food forms include dairy products such as ice cream and yogurt; rice cakes, gums, cookies, cakes, puddings, jellies, bavarois, mousse, mutton, buns, middle, dorayaki, taiyaki, roasted baked, rice crackers, Japanese and Western confectioneries such as ohagi, daifuku, dumpling, zenzai and the like can be mentioned. Examples of beverages include coffee, tea, soft drinks, carbonated drinks, fruit juice drinks and the like. In order to make it into the form of food or beverage, the active ingredient of the blood sugar level increase inhibitor of the present invention may be mixed in any of the production processes of food or beverage. In this case, the sugar which is originally contained in the food or beverage can be used as the active ingredient sugar.
本発明の血糖値上昇抑制剤は、砂糖と砂糖分解酵素の阻害剤と腸管内の砂糖分解酵素とから形成された複合体が砂糖分解酵素の活性を阻害した状態で長時間維持されているので、血糖値上昇抑制効果が長時間持続する。従って、本発明の血糖値上昇抑制剤は、食前10分から6時間までの広い時間範囲の中から摂取時期を選択することができ、糖尿病患者にとって摂取が極めて容易である。 The blood sugar level increase inhibitor of the present invention is maintained for a long time in a state where a complex formed from sugar, a sugar-degrading enzyme inhibitor and a sugar-degrading enzyme in the intestinal tract inhibits the activity of the sugar-degrading enzyme. In addition, the effect of suppressing the increase in blood sugar level lasts for a long time. Therefore, the blood sugar level elevation inhibitor of the present invention can be selected from a wide time range from 10 minutes to 6 hours before a meal, and is very easy for a diabetic patient to take.
以下、本発明の血糖値上昇抑制剤の製造例及び本発明の血糖値上昇抑制剤の効果を示す実施例を具体的に示す。なお、実施例の記載は純粋に発明の理解のためのみに挙げるものであり、本発明はこれらによって限定されるものではない。 Hereinafter, the manufacture example of the blood glucose level rise inhibitor of this invention and the Example which shows the effect of the blood glucose level rise inhibitor of this invention are shown concretely. In addition, description of an Example is given only for understanding of invention, and this invention is not limited by these.
実施例1:複合体形成における砂糖の必要性の確認
砂糖分解酵素源としてラット由来の小腸アセトン粉末を使用し、これにL−アラビノースが結合して複合体を形成するために砂糖が必要であるかどうかを、L−アラビノース及び砂糖分解酵素からなる二成分系におけるL−アラビノースの遊離量と、L−アラビノース、砂糖分解酵素及び砂糖からなる三成分系におけるL−アラビノースの遊離量を経時的にin vitro試験で評価することにより確認した。
Example 1: Confirmation of the necessity of sugar in complex formation Sugar powder is required for the use of rat-derived small intestine acetone powder as a source of sugar-degrading enzyme, to which L-arabinose binds to form a complex. The amount of L-arabinose released in a two-component system consisting of L-arabinose and sugar-degrading enzyme and the amount of L-arabinose released in a three-component system consisting of L-arabinose, sugar-degrading enzyme and sugar over time This was confirmed by evaluation in an in vitro test.
(1)0.1Mマレイン酸緩衝液(pH6.0)に砂糖2gとL−アラビノース200mgを溶解した溶液10mLを準備し、そこに小腸アセトン粉末(ラット)500mgを懸濁して懸濁液1を調製した。対照として、同じ緩衝液にL−アラビノース200mgのみを溶解した溶液10mLを準備し、そこに小腸アセトン粉末(ラット)500mgを懸濁して懸濁液2を調製した。各懸濁液は、37℃で1時間恒温した。 (1) Prepare 10 mL of a solution in which 2 g of sugar and 200 mg of L-arabinose are dissolved in 0.1 M maleate buffer (pH 6.0). Suspension 1 is prepared by suspending 500 mg of small intestine acetone powder (rat) therein. Prepared. As a control, 10 mL of a solution in which only 200 mg of L-arabinose was dissolved in the same buffer was prepared, and 500 mg of small intestine acetone powder (rat) was suspended therein to prepare Suspension 2. Each suspension was incubated at 37 ° C. for 1 hour.
(2)各懸濁液は恒温後、それぞれセルロース透析膜(Ф17.8mm、Cutoff Mw25,000)に移し、密封した。懸濁液1を入れた透析膜は、8gの砂糖を溶解した90mLの0.1Mマレイン酸緩衝液(pH6.0)中に入れ、対照の懸濁液2を入れた透析膜は砂糖を溶解していない90mLの0.1Mマレイン酸緩衝液(pH6.0)中に入れ、それぞれ撹拌しながら37℃で2時間反応させた。 (2) Each suspension was transferred to a cellulose dialysis membrane (Ф 17.8 mm, Cutoff Mw 25,000) after sealing, and sealed. The dialysis membrane containing Suspension 1 was placed in 90 mL of 0.1 M maleic acid buffer (pH 6.0) in which 8 g of sugar was dissolved, and the dialysis membrane containing Control Suspension 2 was dissolved in sugar. It was put in 90 mL of 0.1 M maleic acid buffer (pH 6.0) that had not been reacted, and reacted at 37 ° C. for 2 hours with stirring.
(3)2時間の反応終了後、懸濁液1を入れた透析膜を新たに調製した8gの砂糖を溶解した90mLの0.1Mマレイン酸緩衝液(pH6.0)中に移し、懸濁液2を入れた透析膜を新たに調製した0.1Mマレイン酸緩衝液(pH6.0)中に移し、再び撹拌しながら37℃でさらに2時間反応させた。この(3)の手順は5回繰り返し、計12時間反応させた。12時間の反応中、2時間ごとに緩衝液をサンプリングしておいた。 (3) After completion of the reaction for 2 hours, the dialysis membrane containing the suspension 1 was transferred into 90 mL of 0.1 M maleic acid buffer (pH 6.0) in which 8 g of newly prepared sugar was dissolved, and suspended. The dialysis membrane containing the liquid 2 was transferred into a newly prepared 0.1 M maleate buffer (pH 6.0), and reacted at 37 ° C. for another 2 hours while stirring again. This procedure of (3) was repeated 5 times and allowed to react for a total of 12 hours. During the 12 hour reaction, the buffer was sampled every 2 hours.
(4)サンプリングした各緩衝液は、HPLCで分析し、緩衝液中に遊離したL−アラビノース量を求めた。これらの2時間ごとの遊離L−アラビノース量のデータから、経過時間ごとに遊離L−アラビノース量をグラフ化し、2時間、4時間、6時間、8時間、10時間及び12時間までに遊離したL−アラビノースの量を求め、反応開始時の懸濁液中のL−アラビノースの量を基準として各時間での各懸濁液中のL−アラビノースの残存率を算出した。その結果を図1に示す。図1中、黒丸は懸濁液1についての結果であり、白四角は対照の懸濁液2についての結果である。 (4) Each sampled buffer solution was analyzed by HPLC to determine the amount of L-arabinose released in the buffer solution. From these data on the amount of free L-arabinose every 2 hours, the amount of free L-arabinose was graphed for each elapsed time, and L released by 2, 4, 6, 8, 10, and 12 hours. -The amount of arabinose was determined, and the residual rate of L-arabinose in each suspension at each time was calculated based on the amount of L-arabinose in the suspension at the start of the reaction. The result is shown in FIG. In FIG. 1, black circles are the results for the suspension 1, and white squares are the results for the control suspension 2.
図1から、L−アラビノース及び砂糖分解酵素からなる二成分系の懸濁液2に比べて、L−アラビノース及び砂糖分解酵素に加えて砂糖をさらに含む三成分系の懸濁液1はL−アラビノースを遊離しにくいことがわかる。このことから、L−アラビノースと砂糖分解酵素が複合体を形成するためには砂糖が必要であると言える。 From FIG. 1, compared with the two-component suspension 2 composed of L-arabinose and sugar-degrading enzyme, the three-component suspension 1 further containing sugar in addition to L-arabinose and sugar-degrading enzyme is L- It turns out that arabinose is hard to release. From this, it can be said that sugar is necessary for L-arabinose and a sugar-degrading enzyme to form a complex.
実施例2:複合体の維持時間の確認
砂糖分解酵素源としてラット由来の小腸アセトン粉末を使用し、砂糖分解酵素と砂糖とL−アラビノースが複合体を形成してからその状態を維持し続ける時間を、砂糖及び砂糖分解酵素からなる二成分系と比較した砂糖、砂糖分解酵素及びL−アラビノースからなる三成分系における砂糖分解酵素の阻害率を経時的にin vitro試験で評価することにより確認した。
Example 2: Confirmation of the maintenance time of the complex Using rat intestinal acetone powder as the source of the sugar-degrading enzyme, the time for maintaining the state after the sugar-degrading enzyme, sugar and L-arabinose form a complex Was confirmed by evaluating the inhibition rate of sugar-degrading enzyme in a ternary system consisting of sugar, sugar-degrading enzyme and L-arabinose over time in an in vitro test compared with a two-component system consisting of sugar and sugar-degrading enzyme. .
(1)0.1Mマレイン酸緩衝液(pH6.0)に砂糖2gとL−アラビノース200mgを溶解した溶液10mLを準備し、そこに小腸アセトン粉末(ラット)500mgを懸濁して懸濁液1を調製した。対照として、同じ緩衝液に砂糖2gのみを溶解した溶液10mLを準備し、そこに小腸アセトン粉末(ラット)500mgを懸濁して懸濁液2を調製した。各懸濁液は、37℃で1時間恒温した。 (1) Prepare 10 mL of a solution in which 2 g of sugar and 200 mg of L-arabinose are dissolved in 0.1 M maleate buffer (pH 6.0). Suspension 1 is prepared by suspending 500 mg of small intestine acetone powder (rat) therein. Prepared. As a control, 10 mL of a solution in which only 2 g of sugar was dissolved in the same buffer was prepared, and 500 mg of small intestine acetone powder (rat) was suspended therein to prepare Suspension 2. Each suspension was incubated at 37 ° C. for 1 hour.
(2)各懸濁液は恒温後、それぞれセルロース透析膜(Ф17.8mm、Cutoff Mw25,000)に移し、密封した。各透析膜は、8gの砂糖を溶解した90mLの0.1Mマレイン酸緩衝液(pH6.0)中に入れ、撹拌しながら37℃で2時間反応させた。 (2) Each suspension was transferred to a cellulose dialysis membrane (Ф 17.8 mm, Cutoff Mw 25,000) after sealing, and sealed. Each dialysis membrane was placed in 90 mL of 0.1 M maleate buffer (pH 6.0) in which 8 g of sugar was dissolved, and reacted at 37 ° C. for 2 hours with stirring.
(3)2時間の反応終了後、新たに調製した8gの砂糖を溶解した90mLの0.1Mマレイン酸緩衝液(pH6.0)中に各透析膜を移し、再び撹拌しながら37℃でさらに2時間反応させた。この(3)の手順は4回繰り返し、計10時間反応させた。10時間の反応中、30分ごとに少量(100μL)の緩衝液をサンプリングした。 (3) After completion of the reaction for 2 hours, each dialysis membrane was transferred into 90 mL of 0.1 M maleic acid buffer (pH 6.0) in which 8 g of newly prepared sugar was dissolved, and further stirred at 37 ° C. with stirring. The reaction was performed for 2 hours. This procedure of (3) was repeated 4 times and allowed to react for a total of 10 hours. During the 10 hour reaction, a small amount (100 μL) of buffer was sampled every 30 minutes.
サンプリングした各緩衝液をグルコース測定キット(グルコース(II−テスト、和光純薬)で測定し、各時点におけるグルコース産生量を求めた。これらの30分ごとのグルコース産出量のデータから、経過時間ごとにグルコース産生量をグラフ化し、2時間、4時間、6時間、8時間及び10時間の各時点におけるグルコース産生速度(つまり、砂糖分解速度)をそれらの各々の時点の前2時間にわたるグルコースの増大速度から求めた。また、0時間におけるグルコース産生速度は、反応開始30分後に採取したサンプル緩衝液におけるグルコース産生量を基準とし、対照のグルコース産生速度が不変として補正処理を行って求めた。さらに、各時点における対照の懸濁液2の砂糖分解速度を基準として懸濁液1の砂糖分解速度の抑制率(つまり砂糖分解酵素阻害率)を算出した。その結果を表1に示す。 Each sampled buffer solution was measured with a glucose measurement kit (glucose (II-Test, Wako Pure Chemical Industries), and the amount of glucose produced at each time point was determined. From these glucose output data every 30 minutes, every elapsed time Graph the glucose production in 2 hours, 4 hours, 6 hours, 8 hours and 10 hours at each time point to increase the glucose production rate (ie sugar degradation rate) over 2 hours before each time point. In addition, the glucose production rate at 0 hour was obtained by performing a correction process on the basis of the glucose production rate in the sample buffer collected 30 minutes after the start of the reaction, with the control glucose production rate unchanged. Inhibiting the rate of sugar degradation of suspension 1 relative to the rate of sugar degradation of control suspension 2 at each time point (I.e. sugar degrading enzyme inhibitory rate) was calculated. The results are shown in Table 1.
表1から、砂糖とL−アラビノースを添加して複合体が形成されている懸濁液1の小腸アセトン粉末は、砂糖分解酵素活性が長時間阻害されており、6時間後でも45%の砂糖分解酵素が阻害されていることがわかった。 From Table 1, the small intestine acetone powder of suspension 1 in which a complex is formed by adding sugar and L-arabinose, the sugar-degrading enzyme activity is inhibited for a long time, and 45% of sugar is present even after 6 hours. It was found that the degradation enzyme was inhibited.
実施例3:砂糖の量が血糖値上昇抑制効果に及ぼす影響の確認
砂糖及びL−アラビノースを有効成分とする血糖値上昇抑制剤中の砂糖の量が血糖値上昇抑制効果に及ぼす影響を成人男性を対象としたin vivo試験で検証した。
Example 3: Confirmation of the effect of the amount of sugar on the blood glucose level increase inhibitory effect The effect of the amount of sugar in the blood sugar level increase inhibitor containing sugar and L-arabinose as an active ingredient on the blood glucose level increase inhibitory effect of an adult male This was verified in an in vivo test.
健常な成人男性5名(年齢42.4±6.6歳、BMI23.6±5.2)に血糖値上昇抑制剤として砂糖10gとL−アラビノース粉末0.5g(対砂糖5重量%)、砂糖20gとL−アラビノース粉末1.0g(対砂糖5重量%)、又は砂糖30gとL−アラビノース粉末1.5g(対砂糖5重量%)を水120gに溶解したものを摂取させた。2時間後、食事として砂糖20gを120gの水に溶解したものを摂取させた。その後、2時間にわたって血糖値の変化及び血糖値上昇の最高値を調べた。試験時間中は水道水以外の摂取は行わなかった。対照として、L−アラビノース粉末を含有しない血糖値上昇抑制剤についても試験を行った。血糖値測定にはメディセーフミニGR−102(テルモ)を用いた。これらの試験は同一人に対して4回繰り返し行い、4回の平均値に基づいてグラフ化及び統計処理を行った。その結果を表2及び図2〜4に示す。 5 healthy adult males (age 42.4 ± 6.6 years old, BMI 23.6 ± 5.2) with 10 g sugar and 0.5 g L-arabinose powder (5% by weight sugar) 20 g of sugar and 1.0 g of L-arabinose powder (5% by weight of sugar) or 30 g of sugar and 1.5 g of L-arabinose powder (5% by weight of sugar) dissolved in 120 g of water were ingested. Two hours later, 20 g of sugar dissolved in 120 g of water was ingested as a meal. Thereafter, the change in blood glucose level and the maximum increase in blood glucose level were examined over 2 hours. No intake other than tap water was performed during the test time. As a control, a test was also conducted for a blood sugar level increase inhibitor not containing L-arabinose powder. Medisafe Mini GR-102 (Terumo) was used for blood glucose level measurement. These tests were repeated four times for the same person, and graphing and statistical processing were performed based on the average value of the four times. The results are shown in Table 2 and FIGS.
表2及び図2〜4から、血糖値上昇抑制剤中の砂糖の量が10gでは対照との効果の有意差がないが、20g以上では血糖値上昇抑制効果の有意差があることがわかる。 From Table 2 and FIGS. 2 to 4, it can be seen that there is no significant difference in the effect from the control when the amount of sugar in the blood sugar level increase inhibitor is 10 g, but there is a significant difference in the blood glucose level increase suppressing effect when it is 20 g or more.
実施例4:砂糖に対するL−アラビノースの割合が血糖値上昇抑制効果に及ぼす影響の確認
砂糖及びL−アラビノースを有効成分とする血糖値上昇抑制剤中の砂糖に対するL−アラビノースの割合が血糖値上昇抑制効果に及ぼす影響を成人男性を対象としたin vivo試験で検証した。
Example 4: Confirmation of the influence of the ratio of L-arabinose to sugar on the blood glucose level increase inhibitory effect The ratio of L-arabinose to sugar in the blood sugar level increase inhibitor containing sugar and L-arabinose as an active ingredient increases the blood sugar level. The influence on the inhibitory effect was verified by an in vivo test for adult males.
健常な成人男性5名(年齢42.4±6.6歳、BMI23.6±5.2)に血糖値上昇抑制剤として砂糖20gとL−アラビノース粉末0.6g(対砂糖3重量%)、砂糖20gとL−アラビノース粉末1.0g(対砂糖5重量%)、砂糖20gとL−アラビノース粉末2.0g(対砂糖10重量%)、又は砂糖20gとL−アラビノース粉末3.6g(対砂糖18重量%)を水120gに溶解したものを摂取させた。2時間後、食事として砂糖20gを120gの水に溶解したものを摂取させた。その後、2時間にわたって血糖値の変化及び血糖値上昇の最高値を調べた。試験時間中は水道水以外の摂取は行わなかった。対照として、L−アラビノース粉末を含有しない血糖値上昇抑制剤についても試験を行った。血糖値測定にはメディセーフミニGR−102(テルモ)を用いた。これらの試験は4回繰り返し行い、4回の平均値に基づいてグラフ化及び統計処理を行った。その結果を表3及び図5〜8に示す。 5 healthy adult males (age 42.4 ± 6.6 years old, BMI 23.6 ± 5.2) with 20 g sugar and 0.6 g L-arabinose powder (3% by weight sugar) 20 g of sugar and 1.0 g of L-arabinose powder (5% by weight of sugar), 20 g of sugar and 2.0 g of L-arabinose powder (10% by weight of sugar), or 20 g of sugar and 3.6 g of L-arabinose powder (vs. sugar 18% by weight) dissolved in 120 g of water. Two hours later, 20 g of sugar dissolved in 120 g of water was ingested as a meal. Thereafter, the change in blood glucose level and the maximum increase in blood glucose level were examined over 2 hours. No intake other than tap water was performed during the test time. As a control, a test was also conducted for a blood sugar level increase inhibitor not containing L-arabinose powder. Medisafe Mini GR-102 (Terumo) was used for blood glucose level measurement. These tests were repeated 4 times, and graphing and statistical processing were performed based on the average value of 4 times. The results are shown in Table 3 and FIGS.
表3及び図5〜8から、血糖値上昇抑制剤中の砂糖に対するL−アラビノースの割合が3重量%では対照との血糖値上昇抑制効果の有意差がないが、5重量%以上では効果の有意差があることがわかる。 From Table 3 and FIGS. 5-8, when the ratio of L-arabinose to sugar in the blood sugar level increase inhibitor is 3% by weight, there is no significant difference in the blood glucose level increase inhibitory effect from the control. It can be seen that there is a significant difference.
実施例5:実際の摂取状況での血糖値上昇抑制効果の確認
実施例3及び4では食事として砂糖を水に溶解したものを摂取したが、実施例5では実際の摂取状況を模倣するため、食事として市販食品を使用した。また、被験者の数を増やした。
Example 5: Confirmation of blood glucose level increase inhibitory effect in actual ingestion situation In Examples 3 and 4, sugar was dissolved in water as a meal. In Example 5, in order to imitate the actual ingestion situation, Commercial food was used as a meal. In addition, the number of subjects was increased.
健常な成人男女20名(年齢42.2±10.6歳、BMI21.3±4.5)に、砂糖40gを水110gに溶解して与え、摂取直前と摂取後2時間までの血糖値変化を調べた。この結果に基づき、年齢、性別、血糖値上昇値(60mg/dL以上と60mg/dL未満)がそれぞれ偏ることのないように二つの群(第一群及び第二群)に分けた。 20 healthy adult males and females (age 42.2 ± 10.6 years old, BMI 21.3 ± 4.5) given 40 g of sugar dissolved in 110 g of water, and blood sugar level changes immediately before ingestion and up to 2 hours after ingestion I investigated. Based on this result, it divided into two groups (1st group and 2nd group) so that age, sex, and a blood glucose level raise value (60 mg / dL or more and less than 60 mg / dL) may not be biased, respectively.
本発明の血糖値上昇抑制剤として、砂糖40gとL−アラビノース粉末2.0gを水110gに溶解したものを準備し、これを第一食と称することにした。また、対照として、砂糖40gを水110gに溶解したものを準備し、これを第二食と称することにした。第一群には第一食を、第二群には第二食を与えた。 As the blood sugar level increase inhibitor of the present invention, a solution prepared by dissolving 40 g of sugar and 2.0 g of L-arabinose powder in 110 g of water was prepared, and this was referred to as the first meal. As a control, a solution prepared by dissolving 40 g of sugar in 110 g of water was prepared and referred to as a second meal. The first group was given a first meal and the second group was given a second meal.
2時間後、両群に食事としてどら焼き(駿河屋)90g(砂糖含有量40g)を摂取させ、その後、2時間にわたって血糖値の変化及び血糖値上昇の最高値を調べた。血糖値測定にはメディセーフミニGR−102(テルモ)を用いた。また、試験時間中は水道水以外の摂取は禁止した。 Two hours later, both groups received 90 g of Dorayaki (Surugaya) (sugar content 40 g) as a meal, and then examined the change in blood glucose level and the maximum increase in blood glucose level over 2 hours. Medisafe Mini GR-102 (Terumo) was used for blood glucose level measurement. In addition, intake other than tap water was prohibited during the test period.
この試験から7日の冷却期間を置いて、この試験を繰り返した。試験繰り返しの際は、第一群には第二食を、第二群には第一食を与えた。 The test was repeated with a 7 day cooling period from this test. When the test was repeated, the first group was given a second meal and the second group was given the first meal.
得られた血糖値データは、クロスオーバーを考慮したt検定(中里 溥志,健康・栄養食品研究,7,71−78(2004))により分析し、対照(第二食)と比較した本発明の血糖値上昇抑制剤(第一食)の血糖値上昇抑制効果の有意性を検討した。但し、データの解析終了までは、被験者、試験実施者、データ解析者のいずれに対しても、第一食と第二食の内容を伏せた。結果を表4及び図9に示す。 The obtained blood glucose level data were analyzed by a t-test taking into account the crossover (Takashi Nakazato, Health and Nutrition Food Research, 7, 71-78 (2004)) and compared with the control (second meal) of the present invention. The significance of the blood glucose level increase inhibitory effect of the blood glucose level increase inhibitor (first meal) was examined. However, until the end of data analysis, the contents of the first meal and the second meal were concealed to all of the subjects, the tester, and the data analyst. The results are shown in Table 4 and FIG.
表4及び図9から、本発明の血糖値上昇抑制剤は食事として市販食品を使用した実際の摂取状況でも十分な血糖値上昇抑制効果を有することがわかる。 From Table 4 and FIG. 9, it can be seen that the blood sugar level increase inhibitor of the present invention has a sufficient blood glucose level increase suppressing effect even in an actual ingestion situation using a commercial food as a meal.
実施例6
様々な食品及び飲料の形態での本発明の血糖値上昇抑制剤の効果の確認
本発明の血糖値上昇抑制剤を様々な食品及び飲料の形態に作り、これらを食前2時間に摂取した場合の血糖値上昇抑制効果を確認した。
Example 6
Confirmation of the effect of the blood sugar level elevation inhibitor of the present invention in various food and beverage forms The blood sugar level elevation inhibitor of the present invention is made into various food and beverage forms, and these are taken in 2 hours before a meal. The blood glucose level increase inhibitory effect was confirmed.
(水羊羹の形の血糖値上昇抑制剤の製造)
水300mLと寒天4gを鍋で加熱し寒天を溶解した。これに、市販の餡子(砂糖含量40重量%)400gとL−アラビノース粉末を8gを添加し、軽く加熱しながら均一に混合してから火を止めた。これを100gずつ八つの型に流し込み、冷却して、1個あたり砂糖20g、L−アラビノース1gを含む水羊羹を得た。
(Manufacture of an inhibitor of blood sugar level rise in the form of water sheep)
300 mL of water and 4 g of agar were heated in a pan to dissolve the agar. To this, 400 g of commercially available coconut (
(リンゴゼリーの形の血糖値上昇抑制剤の製造)
グラニュー糖80gとL−アラビノース粉末4g、ゲルメイトKB(新日本製薬株式会社)1.5gを水52gと共に鍋に入れ、軽くかき混ぜながら80℃で5分間加熱した。加熱をやめた後、そこにリンゴ果汁30gとクエン酸0.15gを添加し、100gずつ四つの型に流し込み十分放冷した後、冷蔵庫で冷やして、1個あたり砂糖20g、L−アラビノース1gを含むリンゴゼリーを得た。
(Manufacture of blood sugar level increase inhibitor in the form of apple jelly)
80 g of granulated sugar, 4 g of L-arabinose powder and 1.5 g of Gelmate KB (Shin Nippon Pharmaceutical Co., Ltd.) were placed in a pan together with 52 g of water, and heated at 80 ° C. for 5 minutes while stirring gently. After stopping the heating, add 30 g of apple juice and 0.15 g of citric acid, pour 100 g into 4 molds, allow to cool, and cool in the refrigerator to contain 20 g of sugar and 1 g of L-arabinose. Got apple jelly.
(落雁の形の血糖値上昇抑制剤の製造)
粉糖20gとL−アラビノース粉末1gを予めよく混合した後、水約4gを添加しながら更によく混ぜた。そこに微甚粉30gを加えて更に混ぜ合わせた後、型詰めして成形した。成形物は型から取り出し、一晩乾燥させ、砂糖20g、L−アラビノース1gを含む落雁を得た。
(Manufacture of blood glucose level rise inhibitor in the form of decoctions)
20 g of powdered sugar and 1 g of L-arabinose powder were mixed well in advance, and further mixed well while adding about 4 g of water. 30 g of fine powder was added thereto and further mixed, and then molded and molded. The molded product was taken out of the mold and dried overnight to obtain a drop of candy containing 20 g of sugar and 1 g of L-arabinose.
(最中の形の血糖値上昇抑制剤の製造)
小豆200gを煮上げた後、グラニュー糖80gを加え少し加熱してから、一晩寝かせた。これを鍋にいれ、水80mLとグラニュー糖100gとL−アラビノース13gを加えて、15分ほど加熱した後、煮詰めた寒天液(2〜3gの寒天を溶かし、砂糖80gを加えたもの)と混ぜ合わせて練りつぶし、最中餡を作った。このうち50gを市販の最中種に入れ、砂糖20g、L−アラビノース1gを含む最中を得た。
(Manufacture of blood sugar level increase inhibitor in the middle)
After 200g of red beans were boiled, 80g of granulated sugar was added and heated a little, then allowed to sleep overnight. Put this in a pan, add 80 mL of water, 100 g of granulated sugar and 13 g of L-arabinose, heat for about 15 minutes, and then mix with boiled agar liquid (dissolved 2-3 g of agar and added with 80 g of sugar). We kneaded together and made a rice cake in the middle. Among these, 50 g was put into a commercially available middle seed, and a middle containing 20 g of sugar and 1 g of L-arabinose was obtained.
(炭酸飲料の形の血糖値上昇抑制剤の製造)
市販の炭酸水500mLにグラニュー糖20gとL−アラビノース粉末1gを添加して十分に混合し、さらにレモン果汁20gを添加し、砂糖20g、L−アラビノース1gを含む炭酸飲料を得た。
(Manufacture of blood sugar level increase inhibitor in the form of carbonated beverages)
To 500 mL of commercially available carbonated water, 20 g of granulated sugar and 1 g of L-arabinose powder were added and mixed well. Further, 20 g of lemon juice was added to obtain a carbonated beverage containing 20 g of sugar and 1 g of L-arabinose.
健常な成人男性5名(年齢42.4±6.6歳、BMI23.6±5.2)に血糖値上昇抑制剤として上記の水羊羹、リンゴゼリー、落雁、最中又は炭酸飲料を摂取させた。2時間後、食事として砂糖20gを120gの水に溶解したものを摂取させた。その後、2時間にわたって血糖値の変化及び血糖値上昇の最高値を調べた。試験時間中は水道水以外の摂取は行わなかった。対照として、砂糖20gを水120gに溶解した、L−アラビノース粉末を含有しない血糖値上昇抑制剤についても試験を行った。血糖値測定にはメディセーフミニGR−102(テルモ)を用いた。これらの試験は同一人に対して4回繰り返し行い、4回の平均値に基づいてグラフ化及び統計処理を行った。その結果を表5に示す。 Five healthy adult males (age 42.4 ± 6.6 years old, BMI 23.6 ± 5.2) were allowed to take the above-mentioned water goat candy, apple jelly, decoction, during or as carbonated drinks It was. Two hours later, 20 g of sugar dissolved in 120 g of water was ingested as a meal. Thereafter, the change in blood glucose level and the maximum increase in blood glucose level were examined over 2 hours. No intake other than tap water was performed during the test time. As a control, a test was also conducted for a blood sugar level increase inhibitor containing 20 g of sugar dissolved in 120 g of water and not containing L-arabinose powder. Medisafe Mini GR-102 (Terumo) was used for blood glucose level measurement. These tests were repeated four times for the same person, and graphing and statistical processing were performed based on the average value of the four times. The results are shown in Table 5.
表5から、本発明の血糖値上昇抑制剤は、様々な食品及び飲料の形態であっても十分な血糖値上昇抑制効果を有することがわかる。 From Table 5, it can be seen that the blood glucose level elevation inhibitor of the present invention has a sufficient blood glucose level elevation inhibitory effect even in various food and beverage forms.
本発明の血糖値上昇抑制剤は、比較的多量の砂糖とL−アラビノースに代表される砂糖分解酵素の不拮抗阻害剤を有効成分として含むため、血糖値上昇抑制効果の持続時間が長く、食前10分から6時間にわたる広い時間範囲のいずれの時点で摂取しても食事の糖質の吸収分解を効果的に阻止することができる。従って、本発明の血糖値上昇抑制剤は、糖尿病患者において食後の血糖値の上昇を抑制するために日常的に使用されることができる。 Since the blood sugar level increase inhibitor of the present invention contains a relatively large amount of sugar and a non-competitive inhibitor of a sugar-degrading enzyme typified by L-arabinose as active ingredients, the duration of the blood sugar level increase suppressing effect is long. Ingestion of carbohydrates in the diet can be effectively prevented at any point in the wide time range from 10 minutes to 6 hours. Therefore, the blood glucose level elevation inhibitor of the present invention can be used on a daily basis in diabetes patients in order to suppress an increase in blood glucose level after meals.
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CN104739848A (en) * | 2015-04-07 | 2015-07-01 | 福州乾正药业有限公司 | Composition containing L-arabinose and tagatose as well as preparation method and drug application of composition |
USD824779S1 (en) | 2016-12-22 | 2018-08-07 | 800 Sylvan Avenue | Package |
USD826720S1 (en) | 2016-12-22 | 2018-08-28 | Conopco, Inc. | Bottle |
US11883835B2 (en) | 2016-12-22 | 2024-01-30 | Conopco, Inc. | Shell container suitable for housing a discrete refill container |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
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EP3453262B1 (en) * | 2016-05-04 | 2023-05-03 | Cj Cheiljedang Corporation | Health functional food for inhibiting rise of blood glucose containing coffee and tagatose |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
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JPH0665080A (en) * | 1992-03-10 | 1994-03-08 | Godo Shiyusei Kk | Agent for prevention and treatment of hyperglycemia-relating disease containing alpha-glucosidase inhibitor and health food |
JP5025847B2 (en) * | 2000-11-15 | 2012-09-12 | 信 藤井 | Diabetes treatment |
JP2002176937A (en) * | 2000-12-12 | 2002-06-25 | Taito Co Ltd | Low-sweetness and low-caloric food |
JP2005289847A (en) * | 2004-03-31 | 2005-10-20 | Unitika Ltd | Blood sugar level rising inhibitor |
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2007
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104739848A (en) * | 2015-04-07 | 2015-07-01 | 福州乾正药业有限公司 | Composition containing L-arabinose and tagatose as well as preparation method and drug application of composition |
USD824779S1 (en) | 2016-12-22 | 2018-08-07 | 800 Sylvan Avenue | Package |
USD826720S1 (en) | 2016-12-22 | 2018-08-28 | Conopco, Inc. | Bottle |
US11883835B2 (en) | 2016-12-22 | 2024-01-30 | Conopco, Inc. | Shell container suitable for housing a discrete refill container |
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JP2008189638A (en) | 2008-08-21 |
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